1. Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention relates to benzimidazole acetic acid compounds which function as antagonists of the Chemoattractant Receptor-homologous molecule expressed on T-Helper type 2 cells (CRTH2) receptor. The invention also relates to the use of these compounds to inhibit the binding of prostaglandin D2 and its metabolites to the CRTH2 receptor and to treat disorders responsive to such inhibition.
2. Related Art
The CRTH2 receptor binds prostaglandin D2 (PGD2) and its metabolites. Efforts have been made to inhibit the binding of PGD2 to the CRTH2 receptor in order to treat disorders and diseases related to excess levels of PGD2.
Elevated PGD2 is thought to play a causative role in both asthma and atopic dermatitis. For example, PGD2 is one of the major prostanoids released by mast cells in the asthmatic lung and this molecule is found at high levels in the bronchial fluid of asthmatics (Liu et al., Am. Rev. Respir. Dis. 142:126 (1990)). Evidence of a role of PGD2 in asthma is provided by a recent publication examining the effects of overexpression of prostaglandin D synthase on induction of allergic asthma in transgenic mice (Fujitani, J. Immunol. 168:443 (2002)). After allergen challenge, these animals had increased PGD2 in the lungs, and the number of Th2 cells and eosinophils were greatly elevated relative to non-transgenic animals. These results are
PGD2 can bind to two G-protein coupled receptors, DP (Boie et al., J. Biol. Chem. 270:18910 (1995)) and CRTH2 (Nagata et al., J. Immunol. 162:1278 (1999); Hirai et al., J. Exp. Med. 193:255 (2001)). The latter receptor might play a particularly important role in diseases such as asthma and atopic dermatitis that are characterized by Th2 cell involvement, since Th2 cell chemotaxis in response to PGD2 appears to be mediated by CRTH2 (Hirai et al., above). Moreover, eosinophils, the major inflammatory cell type seen in asthmatic lungs, show a CRTH2-mediated chemotactic response to PGD2 (Hirai et al.) and certain thromboxane metabolites (Bohm et al., J. Biol. Chem. 279:7663 (2004)).
JP2000143635 and JP2000095767 disclose compounds of the following formula that are neovascularization inhibitors:
wherein A is a substituted or unsubstituted phenyl ring; B is a substituted or unsubstituted cyclyl; R4 and R6 are H, optionally substituted C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, optionally substituted C7-13 aralkyl, or C2-7 alkoxycarbonyl; R5 is H, halo, optionally substituted C1-6 alkyl, C1-6 alkoxy, C2-7 alkoxycarbonyl, mono- or di(C1-6 alkyl)amino, or optionally substituted carbamoyl; X is a direct bond, C1-6 alkylene, C2-6 alkenylene, C1-6 alkylene-aminocarbonyl, or C1-6 alkylene-oxycarbonylamino; Y is CO, SO2, NHCO, C1-6 alkylenecarbonyl, C2-6 alkenylenecarbonyl, or C1-6 alkylene.
JP62024244 discloses compounds of the following formula that can be used as part of photographic photosensitive materials:
wherein Y1 is H, R1, COR2, or SO2R3; Y2 is H, NHR4, NHCOR5, or NHSO2R6; R1, R2, R3, R5, and R6 are aliphatic or aromatic moieties; R4 is H or R1; Y1 and Y2 cannot be H simultaneously; when R4 is H, Y1 is not H; X is halo, alkyl, aryl, aralkyl, alkoxy, OH, NO2, or CN; and n is 0, 1, or 2.
U.S. Pat. No. 6,121,308 discloses compounds of the following formula that can be used to treat thrombotic disease:Ra-Het-B—Ar-Ewherein B denotes an ethylene group optionally substituted by one or two C1-3 alkyl groups, wherein a methylene group of the ethylene group, which is linked to either the Het or Ar group, may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, carbonyl or —NR1 group, whilst R1 denotes a hydrogen atom or a C1-6-alkyl group;    B also denotes a straight-chained C3-5-alkylene group, in which a methylene group, which is linked neither to the Het group nor to the Ar group, is replaced by an —NR1 group wherein R1 is as hereinbefore defined;    E denotes a cyano or RbNH—C(═NH)—group wherein Rb denotes a hydrogen atom, a hydroxy group, a C1-3-alkyl group or a group which may be cleaved in vivo;    Ar denotes a phenylene or naphthylene group optionally substituted by a fluorine, chlorine or bromine atom, or by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C1-3 alkyl group;    Het denotes a bicyclic heterocycle of the formula
wherein X denotes a nitrogen atom or a methine group optionally substituted by a C1-3-alkyl group and Y denotes an imino group optionally substituted by a C1-5-alkyl or C3-7-cycloalkyl group, an oxygen or sulphur atom or X denotes a nitrogen atom and Y denotes an imino group substituted by a C1-5-alkyl or C3-7-cycloalkyl group, wherein the alkyl and cycloalkyl substituent in each case is substituted by a carboxy group or a group which can be converted in vivo into a carboxy group, wherein additionally in one of the abovementioned heterocycles a non-angular methine group may be replaced by a nitrogen atom;or Het denotes a group of the formulae
wherein R1 is as hereinbefore defined, and Ra denotes a phenyl-C1-3 alkoxy group, an amino group, a C1-3-alkylamino group, which is additionally substituted at the nitrogen atom by a phenyl-C1-3 alkyl group, a R3-CO-R4N or R3-SO2-R4N group wherein R3 denotes a C1-5-alkyl, phenyl-C1-3-alkyl, C3-7-cycloalkyl, phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, tetrahydroquinolyl or tetrahydroisoquinolyl group and R4 denotes a hydrogen atom, C1-5-alkyl or phenyl-C1-3-alkyl group, each of which is substituted in the alkyl moiety by a group which may be converted in vivo into a carboxy group, by a carboxy or tetrazolyl group, by an aminocarbonyl or C1-3-alkylaminocarbonyl group, each of which is additionally substituted at the nitrogen atom by a group which may be converted in vivo into a carboxy-C1-3-alkyl group or by a carboxy group, a C2-5-alkyl group terminally substituted by a di-(C1-3-alkyl)-amino group, or a C3-7-cycloalkyl group.
U.S. Pat. No. 6,114,532 discloses compounds of the following formula that can be used to treat thrombotic disease:
wherein A denotes an oxygen or sulphur atom, a carbonyl, sulphinyl or sulphonyl group, an imino group optionally substituted by a C1-3-alkyl group or a methylene group optionally mono- or disubstituted by a carboxy-C1-3-alkyl- or C1-3-alkoxycarbonyl-C1-3-alkyl group;    Ar denotes a phenylene or naphthylene group each optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C1-3-alkyl- or C1-3-alkoxy group, a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group each optionally substituted in the carbon skeleton by a C1-3-alkyl group;    X denotes a nitrogen atom or an —R1C═ group wherein R1 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a C1-3-alkyl or C1-3-alkoxy group;    Y denotes an oxygen or sulphur atom or an —R2N— group, wherein R2 denotes a hydrogen atom or a C1-5-alkyl group, a C1-3-alkyl group, which is substituted by a phenyl group optionally substituted by a carboxy or C1-3-alkoxycarbonyl group, a C1-5-alkyl group, which is substituted by a carboxy, C1-3-alkoxycarbonyl, carboxy-C1-3-alkoxycarbonyl, C1-3-alkoxycarbonyl-C1-3-alkoxycarbonyl, carboxy-C1-3-alkyl-aminocarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group, or an n-C2-4-alkyl group, which is terminally substituted by a di-(C1-3-alkyl)-amino, pyrrolidino, piperidino, morpholino, piperazino or N—C1-3-alkyl-piperazino group, wherein the abovementioned cyclic groups may additionally be substituted by one or two C1-3-alkyl groups;    Ra denotes a hydrogen atom or a C1-3-alkyl group;    Rb denotes a R3—CO—C3-5-cycloalkylene, R3—SO2—NR4, R3—CO—NR4, R5NR6—CO, R5NR6—SO2— or RNR6—CO—C3-5-cycloalkylene group, wherein R3 denotes a C1-6-alkyl- or C5-7-cycloalkyl group, a C1-3-alkyl group, which is substituted by a C5-7-cyclo-alkyl, phenyl, C1-3-alkylamino, di-(C1-3-alkyl)-amino, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonylamino, phenylsulphonylamino or tetrazolyl group, a C1-3-alkyl group, which is substituted by a carboxy, C1-3-alkoxycarbonyl, carboxy-C1-3-alkoxy or C1-3-alkoxy-carbonyl-C1-3-alkoxy group, a C1-3-alkyl group, which is substituted by an imidazolyl or benzimidazolyl group, wherein the imidazole moiety of the abovementioned groups may be substituted by one or two C1-3-alkyl groups or by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, a phenyl group optionally mono or disubstituted by C1-3-alkyl, C1-3-alkoxy, trifluoromethyl, carboxy or C1-3-alkoxycarbonyl groups, wherein the substituents may be identical or different, a phenyl group substituted by 3 or 4 methyl groups, a naphthyl, pyridinyl, pyrazolyl, quinolyl or isoquinolyl group each optionally substituted by a C1-3-alkyl group;    R4 denotes a hydrogen atom, a C1-5-alkyl or C5-7-cycloalkyl group, a C1-5-alkyl group, which is substituted by a carboxy group or by a C1-5-alkoxycarbonyl group wherein the alkoxy moiety in the 2 or 3 position may additionally be substituted by a hydroxy group, a C1-3-alkyl group, which is substituted by an aminocarbonyl, hydroxyaminocarbonyl, C1-3-alkylamino-carbonyl, di-(C1-3-alkyl)-aminocarbonyl or C5-7-alkylene-iminocarbonyl group, wherein the C6-7-alkyleneimino moiety may additionally be substituted in the 4 position by a di-(C1-3-alkyl)-amino group, an optionally phenyl-substituted C1-3-alkyl group, which is substituted in the alkyl moiety by a carboxy-C1-3-alkoxycarbonyl, C1-3-alkoxycarbonyl-C1-3-alkoxycarbonyl, carboxy-C1-3-alkylaminocarbonyl, N—(C1-3-alkyl)-carboxy-C1-3-alkylaminocarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl, N—(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl, morpholinocarbonyl or 4-(C1-3-alkyl)-piperazinocarbonyl group, a C1-3-alkyl group, which is substituted by a carboxy-C1-3-alkylaminocarbonyl, N—(C1-3-alkyl)-carboxy-C1-3-alkylaminocarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl or N—(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino-carbonyl group, which are additionally substituted at a carbon atom of the alkylamino moiety by a carboxy or C1-3-alkoxycarbonyl group, a C1-3-alkyl group, which is substituted by a di-(C1-3-alkyl)-aminocarbonyl group wherein an alkyl moiety may additionally be substituted in the 2 or 3 position by a di-(C1-3-alkyl)-amino group, a C1-3-alkyl group, which is substituted by a 4-(morpholinocarbonyl-C1-3-alkyl)-piperazinocarbonyl, N—(C1-3-alkyl)-pyrrolidinyl or N—(C1-3-alkyl)-piperidinyl group, or an n-C2-4-alkyl group, which is terminally substituted by a di-(C1-3-alkyl)-amino, C5-7-alkyleneimino or morpholino group;    R5 denotes a C1-5-alkyl or C5-7-cycloalkyl group, a phenyl-C1-3-alkyl group, which may be substituted in the alkyl moiety by a carboxy or C1-3-alkoxycarbonyl group, an n-C2-4-alkyl group, which is substituted in the 2, 3 or 4 position by a hydroxy, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, a phenyl group optionally mono or disubstituted by a C1-3-alkyl, C1-3-alkoxy, trifluoromethyl, carboxy or C1-3-alkoxycarbonyl group, wherein the substituents may be identical or different, a phenyl group substituted by 3 or 4 methyl groups, a naphthyl, pyridinyl, quinolyl or isoquinolyl group;    R6 denotes a C1-5-alkyl group optionally substituted by a carboxy or C1-3-alkoxycarbonyl group, a C1-3-alkyl group, which is substituted in the alkyl moiety by a C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, carboxy-C1-3-alkylaminocarbonyl or C1-3-alkyloxycarbonyl-C1-3-alkylaminocarbonyl group, or an n-C2-4-alkyl group, which is substituted in the 2, 3 or 4 position by a hydroxy, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, or one of the groups R5 or R6 denotes a hydrogen atom, wherein the other one of the groups has the meanings given for R5 and R6 hereinbefore, or R5 and R6 together with the nitrogen atom between them denote a pyrrolidino or piperidino group optionally substituted by one or two C1-3-alkyl groups, which may additionally be substituted by a carboxy-C1-3-alkyl or C1-3-alkoxy-C1-3-alkyl group or on to which a benzene ring may be condensed via two adjacent carbon atoms, or Rb denotes an amino, C1-3-alkylamino or C5-7-cycloalkyl-amino group, which may be substituted at the nitrogen atom by a phenylaminocarbonyl, N-phenyl-C1-3-alkylaminocarbonyl, phenylsulphonylamino-C1-3-alkylcarbonyl, C1-3-alkyloxycarbonyl-C1-3-alkyl, N—(C3-5-cycloalkyl)-C1-3-alkylamino-carbonyl, N-(hydroxycarbonyl-C1-3-alkyl)-aminocarbonyl, N—(C1-3-alkoxycarbonyl-C1-3-alkyl)-aminocarbonyl-C3-5-cyclo-alkylamino group, a piperidino group substituted in the 4 position by a di-(C1-3-alkyl)-amino group, a piperazino group substituted in the 4 position by a C1-3-alkyl group, a C2-4-alkylsulphonyl group, which is substituted in the 2, 3 or 4 position by a di-(C1-3-alkyl)-amino group, a 4-oxo-3,4-dihydro-phthalazinyl-1-yl or 4-oxo-2,3-diaza-spiro[5.5]undec-1-en-1-yl group, a methyl group substituted by a C5-7-cycloalkyleneiminocarbonyl group wherein the methyl group is substituted by a carboxy-C1-3-alkyl or C1-3-alkoxy-C1-3-alkyl group, a carbonyl or methyl group substituted by a C3-5-cycloalkyl or C3-5-alkyl group, wherein the cycloalkyl moiety may additionally be substituted by a C1-3-alkyl, carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group and the methyl moiety is substituted by a C1-3-alkoxy or C1-4-alkylamino group, a C5-7-cycloalkyl-N-(carboxy-C1-3-alkoxy)-iminomethylene or C5-7-cycloalkyl-N—(C1-3-alkoxycarbonyl-C1-3-alkoxy)-iminomethylene group, which may additionally be substituted in the cycloalkyl moiety by a C1-3-alkyl group, a phosphinyl group, which is substituted by a C1-6-alkyl or C5-7-cycloalkyl group and by a hydroxy, C1-3-alkoxy, carboxy-C1-3-alkoxy or C1-3-alkoxycarbonyl-C1-3-alkoxy group, a piperidino group wherein in the 2 position a methylene group is replaced by a carbonyl or sulphonyl group, a tetrazolyl group optionally substituted by a C1-5-alkyl group, a phenyl or phenylsulphonyl group optionally mono or disubstituted by a C1-3-alkyl, C1-3-alkoxy, trifluoromethyl, carboxy or C1-3-alkoxycarbonyl group, wherein the substituents may be identical or different, a sulphimidoyl group, which is substituted at the sulphur atom by a C5-7-cycloalkyl group and may additionally be substituted at the nitrogen atom by a C2-4-alkanoyl, carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl, carboxy-C2-4-alkanoyl or C1-3-alkoxycarbonyl-C2-4-alkanoyl group, an imidazolyl group substituted in the 1 position by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, which may additionally be substituted by a C1-5-alkyl group, a C1-3-alkoxycarbonyl-C1-3-alkyl group, which is substituted in the alkyl moiety by a C5-7-cycloalkylaminocarbonyl group, a C1-3-alkyl group, which is substituted by a 1-imidazolyl group, wherein the imidazolyl moiety may additionally be substituted by one or two C1-3-alkyl groups, or in the 2 position by a 1-benzimidazolyl group substituted by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, or a furanyl-1-pyrazolyl group optionally substituted by a C1-3-alkyl group; and    Rc denotes a cyano group or an amidino group, which may be substituted by a hydroxy group, by one or two C1-3-alkyl groups, by one or two C1-8-alkoxycarbonyl groups or by a group which can be cleaved in vivo.
WO 97/10219 discloses compounds of the following formula that can be used to treat metabolic bone disease:
wherein R1 is acyl, lower alkenyl or lower alkyl optionally substituted with substituent(s) selected from the group consisting of aryl, substituted aryl, a heterocyclic group, a substituted heterocyclic group, hydroxy, substituted hydroxy, cyano, halogen, amino, substituted amino, acyl, mercapto, substituted mercapto, hydroxyamidino, substituted hydroxyamidino, and substituted hydrazino, and    R2 is hydrogen, lower alkyl, hydroxy(lower)alkyl, halo(lower)alkyl, lower alkoxy, lower alkylthio, acyl, or cyano, or    R1 and R2 are taken together to form lower alkylene or lower alkenylene, each of which may include O, S, or N-R5 in the chain, in which R5 is hydrogen or lower alkyl,    R3 is hydrogen or halogen,    R4 is a heterocyclic group or aryl, each of which may be substituted with suitable substituent(s), and    A is
in which R9 is hydrogen, lower alkyl, or substituted lower alkyl, and    R10 is hydrogen, lower alkyl, or substituted lower alkyl.
U.S. Pat. No. 5,612,360 discloses compounds of the following formula that are angiotensin II receptor antagonists:
wherein R1 is CO2H, SO3H, PO3H2, CONHSO2R8, or 5-tetrazolyl;    R2 is H, —OH, —OCOCH3, halo, C1-C4 alkyl, or C1-C4 alkoxy;    R3 is
    X is —(CH2)mCONH—, —(CH2)mNHCO—, —CH2—, —O—, —NH—, or —(CH2)mCO—;    R4 is
C4-C9 straight chain alkyl, or C4-C9 straight chain trifluoroalkyl providing when R4 is a C4-C9 straight chain alkyl or trifluoroalkyl R3 must be (a) or (d);    R5 is H, C1-C5 alkyl, C1-C5 trifluoroalkyl, (CF2)nCF3, benzyl, —(CH2)mN(C1-C3 alkyl)2, —(CH2)mNH(C1-C3 alkyl), —CH2-1-pyrrolidine, —(CH2)nCO2H, or
    R6 is (CH2)pR1, —CONH(C1-C4 alkyl), —CONH(C1-C4 trifluoroalkyl), —COO(C1-C4 alkyl), —COO(C1-C4 trifluoroalkyl), —CONH(hydroxy-C1-C4 alkyl),
    R7 is C4-C9 straight chain alkyl, C4-C9 straight chain trifluoroalkyl, C4-C9 straight chain alkenyl, or C4-C9 straight chain trifluoroalkenyl;    R8 is phenyl, C1-C4 alkyl substituted phenyl, C1-C5 alkyl, or C1-C5 trifluoroalkyl;    R9 is (CH2)pR1, or C1-C4 alkyl;    R10 is H or C1-C3 alkyl;    R11 is H, C1-C4 alkyl, halo, or —(CH2)r phenyl;    R12 is H, —(CH2)pR1, C1-C7 alkyl, C1-C7 trifluoroalkyl, halo, substituted or unsubstituted phenyl, 3-pyridyl, 2-pyrimidyl, furanyl, oxazolyl, isoxazolyl, a substituted or unsubstituted fused bicyclic, a substituted or unsubstituted fused tricyclic, or when m is 0, 4,4-ethylenedioxy;    R13 is O or S;    R14 is H or CH3;    R15 is H or —(CH2)qR16;    R16 is OH, NH2, or CO2H;    R17 is H, OH, C1-C4 alkoxy, CO2H, SO3H, PO3H2, CONHSO2R8, or tetrazolyl;    Y is a R group of a naturally occurring amino acid;    X′ is —O—, —(CH2)p—, or —S—;    m is independently 0 or 1;    n is independently 1, 2 or 3;    p is independently 0, 1, 2, 3 or 4;    q is 1, 2, 3,or 4;    r is independently 0, 1, 2, or 3;    providing when R6 is (1) or (m), and R12 is not H, the carboxy of (m) or the tetrazolyl of (1) is in position 2; and when R6 is (1) or (m), m is 0, and R12 is H, the carboxy of (m) or the tetrazolyl of (1) is in position 2 or 3.
U.S. Pat. No. 3,590,047 discloses compounds of the following formula that have anti-inflammatory, anti-pyretic and analgesic activity:
wherein A is a substituted or unsubstituted aralkyl, heteroaralkyl, aroyl or heteroaroyl radical or a benz derivative thereof;    R2 is hydrogen, hydroxy, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino, di(lower alkyl) amino, lower alkanoylamino, lower alkanoyl, bis(hydroxy lower alkyl)amino, 1-pyrrilidino, 4-methyl-1-piperazinyl, 4-morpholinyl, cyano, trifluoromethyl, halogen, di(lower alkyl) sulfamyl, benzylthio, amino lower alkyl, trifluoromethylthio, benzyloxy, lower alkenyl, lower alkenyloxy, 1-azacyclopropyl, cyclopropyl, cyclopropyl (lower alkoxy), and cyclobutyl (lower alkoxy); the lower alkenyl and alkyl groups containing up to six carbon atoms;    R3 is hydrogen, halogen, trifluoromethyl, a lower alkyl radical, or a lower alkoxy radical;    M is R4 or R5, R4 being amino (provided A is not benzyl at the same time), methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, methylethylamino, methylbutylamino, dibutylamino, glucosamino, glycosylamino, allylamino, phenethylamino, N-ethylphenethylamino, β-hydroxyethylamino, 1-ethyl-2-aminoethylpiperidino, tetrahydrofurfurylamino, 1,2,5,6-tetrahydropyridino, morpholino, N-methylpiperazino, piperazino, N-phenylpiperazino, piperidino, benzylamino, anilino, cyclohexylamino, pyrrolidino, N-hydroxyethylpiperazino, sodium β-sulfoethylamino, N,N-dimethylcarboxamidomethylamino, N,N-diethylaminoethylamino, p-methoxyanilino, and 1-methyl-2-aminoethylpyrrolidino, R5 being hydroxyl or a hydrocarbonoxy group, polyhydroxy lower alkyl, polyhydroxycycloalkyl, polyalkoxy lower alkyl, or a cyclic lower alkylamino lower alkyl radical derived from N-(β-hydroxyethyl) piperidine, N-(β-hydroxyethyl) pyrrolidine, N-(β-hydroxyethyl) morpholine, N-methyl-2-hydroxymethyl pyrrolidine, N-methyl-2-hydroxymethyl piperidine, N-ethyl-3-hydroxy piperidine, 3-hydroxyquinuclidine, and N-(β-hydroxyethyl)-N-methyl piperazine.
WO 02/060438 discloses compounds of the following formula that can be used as integrin antagonists:
wherein R1, R2, R3, R4, and R5 independently represent hydrogen, halogen, alkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl;    R6, R7, R8, and R9 independently represent hydrogen, alkyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, aryl, or aralkyl;    or R6 and R7 are taken together to form —(CH2)p—, where p is 2-8, while R8 and R9 are defined as above; or R8 and R9 are taken together to form —(CH2)q—, where q is 2-8, while R6 and R7 are defined as above; or R6 and R8 are taken together to form —(CH2)r—, while r is zero (a bond), 1, or 2, while R7 and R9 are defined as above;    X represents oxygen, sulfur, —CH2—, —NH—, —(C═O)NH—, or —NH(C═O)—;    n is from 0 to 4;    m is from 0 to 4;    a is 0 or 1;    D represents oxygen;    V is 0 or 1;    R10, R11, R12, and R13 independently represent: hydrogen; hydroxy; alkyl; alkoxy; cycloalkyl; aryl, optionally substituted with one or more of halogen, hydroxy, cyano, alkyl, aryl, alkoxy, haloalkyl, arylalkyl, arylalkoxy, aryloxy, alkylsulfonyl, alkylsulfinyl, alkoxyarylalkyl, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkanoyl; monoalkylamino; dialkylamino; aminoalkyl; monoalkylaminoalkyl; dialkylaminoalkyl; alkanoyl; heteroaryl having 5-14 ring members, optionally substituted with one or more of halogen, hydroxy, cyano, alkyl, aryl, alkoxy, haloalkyl, arylalkyl, arylalkoxy, aryloxy, alkylsulfonyl, alkylsulfinyl, alkoxyarylalkyl, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkanoyl; or
wherein R17 and R18 together form —CH2CH2—O—, —O—CH2CH2—, —O—CH2—O—, or —O—CH2CH2—O—; or    R10 and R12 are taken together to form —(CH2)s—, wherein s is 0 (a bond) or 1 to 4, while R11 and R13 are defined as above; or R10 and R12 are taken together to form a double bond when i is 0 and k is 1, while R11 and R13 are as defined above; or R10 and R11 are taken together to form —(CH2)t—, wherein t is 2 to 8, while R12 and R13 are defined as above, or R12 and R13 are taken together to form —(CH2)u— wherein u is 2 to 8, while R10 and R11 are defined as above;    i is from 0 to 4;    j is from 0 to 4;    k is O or 1;    R14 is hydrogen or a functionality that acts as a prodrug;    W is
wherein Y is —N— or —CH—;    Z is —N— or —CH—;    R15 is hydrogen, halogen, alkyl, aryl, or arylalkyl;    R16 is hydrogen, alkyl, haloalkyl, or halogen;    R19 and R20 are independently hydrogen, halogen, or alkyl;    R27, R28, R29, R30, and R31 are independently hydrogen, halogen, alkyl, alkoxy or aryl; and    o and p are independently 0, 1, or 2.